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Abstract Enfuvirtide (ENF, T-20, Fuzeon) is the first synthetic peptide to be modeled according to the amino acid sequence of HIV-1 heptad repeat 2, which was used to treat cohorts of HIV-1-infected individuals who had failed to respond to treatment with the anti-HIV-1 cocktail HAART. It was reported that when injected subcutaneously, Enfuvirtide reduced viral RNA in patients' blood by 1.96 log(10), leading to a subsequent increase in the number of CD4(+) T cells in the blood. The drug treatment caused adverse effects at the injection site in a small number of treated individuals, and a gradual increase in IgE in the blood during prolonged treatment. Enfuvirtide was approved for treatment of HIV-1 patients who developed resistance to HAART. The present review attempts to explain the adverse effects of Enfuvirtide at the skin site of injection, and the gradual increase in IgE in patients' blood during treatment. These phenomena were reported to resemble the effect of allergens that cause asthma in humans. It is hypothesized that since the amino acid domain of the Asp f1 allergen from Aspergillus fumigatus was identified in the N-terminus of an 18 kDa protein, it may be useful to compare Asp f1 peptide aa 7-22 from the beta-hairpin sequence to the beta-hairpin sequence of the heptad repeat 2 of HIV-1 gp41. The comparison revealed that the amino acid sequence resembles part of the Asp f1 aa 7-22 allergenic domain. The heptad repeat 1 of gp41 also resembles the fungal allergen. It is suggested that the Enfuvirtide peptide be tested experimentally to determine if ENF peptide is capable of binding to IgE antibodies from Enfuvirtide-treated, HIV-1-infected patients, and whether the HR2-derived peptide is capable of inducing basophils that were isolated from healthy individuals and from ENF-treated and untreated HIV-1 patients to release histamine and IL-4.